Cigarette smoke (CS) exposure is associated with increased incidence and severity of airway infections in both children and the elderly. Respiratory syncytial virus (RSV) causes severe bronchiolitis in infants and worsens disease course in chronic obstructive lung disease (COPD) exacerbation in adults. The molecular mechanisms of CS exposure on viral immunity and pathogenesis are not well studied. My studies show that CS exposure has an impressive ability to regulate the innate immunity in the lung after RSV infection. CS enhances the inflammation, alveolar destruction and airway fibrosis caused by RSV. These effects are mediated by type I interferon (IFN) and RIG-like helicase (RLH) antiviral innate immune pathways. CS exposure also results in the persistence of RSV nucleic acids, but not clearance of live virus, in the lung, which we hypothesize chronically activates the RLH innate immune pathways that leads to chronic inflammation. This novel mechanistic pathway may explain the heightened inflammatory response and worsening lung functions in COPD patients with multiple virally-induced exacerbations, and the chronic lung inflammation seen in stable COPD patients. Hypotheses - CS interacts in a synergistic manner with live or UV-inactivated RSV to increase inflammation and remodeling. These interactions are mediated by viral nucleic acid activation of the non-TLR, RIG-like helicase (RLH) innate immune pathway. CS exposure does not alter the clearance of live virus, but allows for the persistence of viral nucleic acids, which contribute to the chronic inflammation and remodeling responses in COPD via RLH pathway activation. Aim 1: Determine if the synergistic interaction between CS and RSV are mediated by RLH pathways. Aim 2: Define the role(s) of type I interferons (IFNa, IFNb) and the type 1 IFN pathway in the enhanced inflammatory and remodeling responses induced by CS and RSV. Aim 3: Define the type I interferon-independent mechanism(s) by which CS exposure enhances the inflammatory response to UV-inactivated RSV. Aim 4: Define the effects of CS exposure on the clearance of live virus and viral nucleic acids in CS- and room air (RA)-exposed lungs. This grant proposes a research mentorship program at Yale University under the primary sponsorship of Professor Jack Elias, a world leader in lung inflammation and fibrosis. Professor George Miller, a recognized leader in viral transcription and replication will serve as co-mentor. We have also enlisted the expertise of three RNA virologists, Drs. Peter Collins, Jeffrey Kahn, and Jack Rose. An advisory committee at Yale will provide scientific and career counseling. The proposed research program as outlined will provide an exciting scientific environment wherein Dr. Dela Cruz can launch his future independent academic career. PUBLIC HEALTH RELEVANCE: Cigarette smoke (CS) exposure when combined with viral respiratory infections results in more severe disease and worsening lung function as seen in CS-exposed infants with respiratory syncytial virus (RSV) associated bronchiolitis and in adults with chronic obstructive pulmonary disease (COPD). We have found that exposure to both CS and RSV leads to an exaggerated increase in lung inflammation and remodeling changes that are mediated by an antiviral immune pathway involving RIG-I-like helicase (RLH) type I interferons and a defect in foreign nucleic acid clearance because of CS exposure. This proposed work in the mouse model will be a stepping stone for human translational research in the hopes of developing new therapeutic approaches for COPD and RSV-related diseases.